Sepsis Research Research Articles

The Surviving Sepsis Campaign: Research Priorities for Coronavirus Disease 2019 in Critical Illness.

To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019.

Sphingolipidomics in Translational Sepsis Research–Biomedical Considerations and Perspectives

Scientific Background: Sphingolipids are a highly diverse group of lipids with respect to physicochemical properties controlling either structure, distribution, or function, all of them regulating cellular response in health and disease. Mass spectrometry, on the other hand, is an analytical technique characterizing ionized molecules or fragments thereof by mass-to-charge ratios, which has been prosperingly developed for rapid and reliable qualitative and quantitative identification of lipid species. Parallel to best performance of in-depth chromatographical separation of lipid classes, preconditions of precise quantitation of unique molecular species by preprocessing of biological samples have to be fulfilled. As a consequence, “lipid profiles” across model systems and human individuals, esp. complex (clinical) samples, have become eminent over the last couple of years due to sensitivity, specificity, and discriminatory capability. Therefore, it is significance to consider the entire experimental strategy from sample collection and preparation, data acquisition, analysis, and interpretation.Areas Covered: In this review, we outline considerations with clinical (i.e., human) samples with special emphasis on sample handling, specific physicochemical properties, target measurements, and resulting profiling of sphingolipids in biomedicine and translational research to maximize sensitivity and specificity as well as to provide robust and reproducible results. A brief commentary is also provided regarding new insights of “clinical sphingolipidomics” in translational sepsis research.Expert Opinion: The role of mass spectrometry of sphingolipids and related species (“sphingolipidomics”) to investigate cellular and compartment-specific response to stress, e.g., in generalized infection and sepsis, is on the rise and the ability to integrate multiple datasets from diverse classes of biomolecules by mass spectrometry measurements and metabolomics will be crucial to fostering our understanding of human health as well as response to disease and treatment.

Survivin and caspases serum protein levels and survivin variants mRNA expression in sepsis

Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases’ responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n = 107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n = 75) and to healthy controls (n = 89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ΔEx3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -ΔΕx3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p < 0.05). Survivin correlated with IL-8 and caspase-9 (p < 0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.

Comparison of response to LPS-induced sepsis in three DBA/2 stocks derived from different sources

Sepsis, one of the most fatal diseases in the world, is known to culminate in multiple organ failure due to an uncontrolled inflammatory response. Hence, the use of animal models in sepsis research is very important to study complex immune responses. The current study was undertaken to compare commercial stocks with KFDA stocks of DBA/2 mice as an animal model for sepsis study. To compare responses of DBA/2 mice to lipopolysaccharides (LPS)-induced sepsis, we measured altered characteristics of various factors associated with sepsis, including survival curves, organ failure and inflammatory response, in DBA/2Korl stock and two commercial stocks (DBA/2A and DBA/2B). Survival rates after LPS exposure were similar for DBA/2Korl and DBA/2B; however, for times over 20 h, survival rates were reduced and concentration dependent in DBA/2A. In order to evaluate multiple organ failure caused by sepsis, H&E stains were evaluated for liver and spleen tissues obtained in the early (2 h) and later (20 h) stages after exposure to LPS; no significant differences were observed between the three stocks. mRNA and protein levels of proinflammatory cytokines were assessed for evaluating inflammatory reactions, and were found to increase in a dose-dependent manner in most DBA/2 mice after LPS treatment. However, no changes were observed in the mRNA levels of proinflammatory cytokines at 20 h after LPS exposure in the DBA/2A stock. The induction of inflammation-mediated factors by LPS exposure did not induce alterations in the mRNA levels of COX-2 and iNOS in all three DBA/2 stocks. Our results indicate that response of DBA/2Korl to LPS-induced sepsis is similar to the two commercial DBA/2 stocks, thus representing its potential as a useful biological resource established in Korea.

Mouse Intensive Care Unit (MICU).

The translation of preclinical results into successful clinical therapies remains a challenge in sepsis research. One reason for this lack of translation might be the discrepancy between preclinical models and the clinical reality: nonresuscitated young healthy rodents in contrast to elderly comorbid patients in an intensive care unit. We introduce the mouse intensive care unit (MICU) as a concept to address the lack of resuscitation in preclinical studies as one of the limiting issues in translational research. The MICU reflects standard procedures of the clinical intensive care unit: fluid resuscitation, lung-protective mechanical ventilation, and hemodynamic monitoring and management, all tailored to organ- and function-specific targets. Thus, the MICU gives an experimental animal the intermediate possibility of recovery and survival due to "patient" management, which is not reflected in less complex experimental scenarios, which either result in acute survival or death.

Analgesia and Humane Endpoints for Rodents in Sepsis Research.

Numerous regulatory bodies around the world require analgesics for rodents undergoing surgery to induce sepsis. Well-controlled pain will decrease morbidity. Options for analgesics include NSAIDs, local analgesics, and opioids. Supportive care can also decrease stress to post-operative animals. As well, humane endpoints should be agreed upon before the study commences so as to alleviate unnecessary pain and distress.

Agent-Based Modeling of Systemic Inflammation: A Pathway Toward Controlling Sepsis.

Despite nearly 50years of research there currently remains no mediator-directed therapy approved for the treatment of sepsis. The failure to effectively translate the copious mechanistic knowledge regarding systemic inflammation to effective therapies is a dramatic example of the translational dilemma. Dynamic computational modeling has been proposed as a vital means of integrating community-wide knowledge into an investigatory framework that allows the application of engineering-like principles to the problem of sepsis. Agent-based modeling is a computational modeling method that has been used to address some of the fundamental issues facing the sepsis research community. This chapter will introduce the rationale to augment traditional research practices with agent-based modeling, describe the basic steps in the construction and use of agent-based models, and provide examples of how the use of agent-based modeling can provide an investigatory pathway to solving the challenge of sepsis.

Pediatric sepsis research in low- and middle-income countries: overcoming challenges.

Pediatric sepsis research in low- and middle-income countries: overcoming challenges.

Research Priorities for U.K. Pediatric Critical Care in 2019: Healthcare Professionals' and Parents' Perspectives.

The Paediatric Intensive Care Society Study Group conducted a research prioritization exercise with the aim to identify and agree research priorities in Pediatric Critical Care in the United Kingdom both from a healthcare professional and parent/caregiver perspective. A modified three-round e-Delphi survey, followed by a survey of parents of the top 20 healthcare professional priorities. U.K. PICUs. U.K. PICU healthcare professionals who are members of the professional society and parents and family members of children, with experience of a U.K. PICU admission. None. Forty-nine healthcare professional submitted topics in round 1, 98 participated in round 2, and 102 in round 3. These topics were categorized into eight broad domain areas, and within these, there were 73 specific topics in round 2. At round 3, 18 topics had a mean score less than 5.5 and were removed, leaving 55 topics for ranking in round 3. Ninety-five parents and family members completed the surveys from at least 17 U.K. PICUs. Both parents and healthcare professional prioritized research topics associated with the PICU workforce. Healthcare professional research priorities reflected issues that impacted on day-to-day management and practice. Parents' prioritized research addressing acute situations such as infection identification of and sepsis management or research addressing long-term outcomes for children and parents after critical illness. Parents prioritized research into longer term outcomes more than healthcare professional. Parental responses showed clear support for the concept of research in PICU, but few novel research questions were proposed. This is the first research prioritization exercise within U.K. PICU setting to include parents' and families' perspectives and compare these with healthcare professional. Results will guide both funders and future researchers.

CD28 Agonism Improves Survival in Immunologically Experienced Septic Mice via IL-10 Released by Foxp3+ Regulatory T Cells.

Immune dysregulation during sepsis is mediated by an imbalance of T cell costimulatory and coinhibitory signaling. CD28 is downregulated during sepsis and is significantly altered on memory versus naive T cells. Thus, to study the role of CD28 during sepsis in a more physiologically relevant context, we developed a "memory mouse" model in which animals are subjected to pathogen infections to generate immunologic memory, followed by sepsis induction via cecal ligation and puncture. Using this system, we show that agonistic anti-CD28 treatment resulted in worsened survival in naive septic animals but conferred a significant survival advantage in immunologically experienced septic animals. Mechanistically, this differential response was driven by the ability of CD28 agonism to elicit IL-10 production from regulatory T cells uniquely in memory but not naive mice. Moreover, elevated IL-10 released by activated regulatory T cells in memory mice inhibited sepsis-induced T cell apoptosis via the antiapoptotic protein Bcl-xL. Together, these data demonstrate that immunologic experience is an important parameter that affects sepsis pathophysiology and can fundamentally change the outcome of modulating the CD28 pathway during sepsis. This study suggests that testing therapeutic strategies in immunologically experienced hosts may be one way to increase the physiologic relevance of rodent models in sepsis research.

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine.

The systemic responses to infection and its progression to sepsis remains poorly understood. Progress in the field has been stifled by the shortcomings of experimental models which include poor replication of the human condition. To address these challenges, we developed and piloted a novel large animal model of severe infection that is capable of generating multi-system clinically relevant data. Male swine (n = 5) were anesthetized, mechanically ventilated, and surgically instrumented for continuous hemodynamic monitoring and serial blood sampling. Animals were inoculated with uropathogenic E. coli by direct injection into the renal parenchyma and were maintained until a priori endpoints were met. The natural history of the infection was studied. Animals were not resuscitated. Multi-system data were collected hourly to 6 hours; all animals were euthanized at predetermined physiologic endpoints. Core body temperature progressively increased from mean (SD) 37.9(0.8)°C at baseline to 43.0(1.2)°C at experiment termination (p = 0.006). Mean arterial pressure did not begin to decline until 6h post inoculation, dropping from 86(9) mmHg at baseline to 28(5) mmHg (p = 0.005) at termination. Blood glucose progressively declined but lactate levels did not elevate until the last hours of the experiment. There were also temporal changes in whole blood concentrations of a number of metabolites including increases in the catecholamine precursors, tyrosine (p = 0.005) and phenylalanine (p = 0.005). Lung, liver, and kidney function parameters worsened as infection progressed and at study termination there was histopathological evidence of injury in these end-organs. We demonstrate a versatile, multi-system, longitudinal, swine model of infection that could be used to further our understanding of the mechanisms that underlie infection-induced multi-organ dysfunction and failure, optimize resuscitation protocols and test therapeutic interventions. Such a model could improve translation of findings from the bench to the bedside, circumventing a significant obstacle in sepsis research.

The promise and pitfalls of composite endpoints in sepsis and COVID-19 clinical trials.

Composite endpoints reveal the tendency for statistical convention to arise locally within subfields. Composites are familiar in cardiovascular trials, yet almost unknown in sepsis. However, the VITAMINS trial in patients with septic shock adopted a composite of mortality and vasopressor-free days, and an ordinal scale describing patient status rapidly became standard in COVID studies. Aware that recent use could incite interest in such endpoints, we are motivated to flag their potential value and pitfalls for sepsis research and COVID studies.

Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?

A recent report by the National Institutes of Health on sepsis research has implied there is a trend to move away from mouse models of sepsis. The most commonly used animal model to study the pathogenesis of human sepsis is cecal ligation and puncture (CLP) in mice. The model has been the mainstay of sepsis research for decades and continues to be considered the gold standard to inform novel pathways of sepsis physiology and its therapeutic direction. As there have been many criticisms of the model, particularly regarding its relevance to human disease, how this model might be repurposed to be more reflective of the human condition begs discussion. In this piece, we compare and contrast the mouse microbiome of the CLP model to the emerging science of the microbiome of human sepsis and discuss the relevance for mice to harbor the specific pathogens present in the human microbiome during sepsis, as well as an underlying disease process to mimic the characteristics of those patients with undesirable outcomes. How to repurpose this model to incorporate these "human factors" is discussed in detail and suggestions offered.

Policy and Pandemic: The Changing Practice of Nephrology During the Coronavirus Disease-2019 Outbreak.

The coronavirus (coronavirus disease-2019) pandemic has changed care delivery for patients with end-stage kidney disease. We explore the US healthcare system as it pertains to dialysis care, including existing policies, modifications implemented in response to the coronavirus disease-2019 crisis, and possible next steps for policy makers and nephrologists. This includes policies related to resource management, use of telemedicine, prioritization of dialysis access procedures, expansion of home dialysis modalities, administrative duties, and quality assessment. The government has already established policies that have instated some flexibilities to help providers focus their response to the crisis. However, future policy during and after the coronavirus disease-2019 pandemic can bolster our ability to optimize care for patients with end-stage kidney disease. Key themes in this perspective are the importance of policy flexibility, clear strategies for emergency preparedness, and robust health systems that maximize accessibility and patient autonomy.

Biomarkers of sepsis: time for a reappraisal

IntroductionSepsis biomarkers can have important diagnostic, therapeutic, and prognostic functions. In a previous review, we identified 3370 references reporting on 178 different biomarkers related to sepsis. In the present review, we evaluate the progress in the research of sepsis biomarkers.MethodsUsing the same methodology as in our previous review, we searched the PubMed database from 2009 until September 2019 using the terms “Biomarker” AND “Sepsis.” There were no restrictions by age or language, and all studies, clinical and experimental, were included.ResultsWe retrieved a total of 5367 new references since our previous review. We identified 258 biomarkers, 80 of which were new compared to our previous list. The majority of biomarkers have been evaluated in fewer than 5 studies, with 81 (31%) being assessed in just a single study. Apart from studies of C-reactive protein (CRP) or procalcitonin (PCT), only 26 biomarkers have been assessed in clinical studies with more than 300 participants. Forty biomarkers have been compared to PCT and/or CRP for their diagnostic value; 9 were shown to have a better diagnostic value for sepsis than either or both of these biomarkers. Forty-four biomarkers have been evaluated for a role in answering a specific clinical question rather than for their general diagnostic or prognostic properties in sepsis.ConclusionsThe number of biomarkers being identified is still increasing although at a slower rate than in the past. Most of the biomarkers have not been well-studied; in particular, the clinical role of these biomarkers needs to be better evaluated.

Microbial exposure increases the magnitude and diversity of peritoneal inflammatory cell infiltrates and cytokine storm during sepsis

Abstract Sepsis – defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection - remains a major healthcare burden and cause of death in the United States and worldwide. While there has been a vast expansion in knowledge regarding the impact of sepsis on the immune system, virtually all preclinical sepsis research to date has relied on using mice housed under specific pathogen-free (SPF) conditions. Environmental pathogen exposure is one important difference between basic human and laboratory mouse biology that must be considered when using mice to evaluate immune system fitness. Interestingly, B6 mice that have been cohoused with pet store mice (to permit microbial transfer and immune system maturation; “CoH” mice) exhibit exaggerated acute hyperinflammation, morbidity, and mortality during cecal ligation and puncture (CLP)-induced polymicrobial sepsis compared to SPF B6 mice. To understand the mechanism of this increased acute response, we examined peritoneal immune cell composition in SPF and CoH mice before and after sepsis induction. CoH mice have more ‘large’ MHC IIloF4/80hi and ‘small’ MHC IIhiF4/80lo peritoneal macrophages (LPM and SPM) and neutrophils than SPF mice at baseline. Upon the induction of polymicrobial-induced peritonitis, there was increased recruitment of neutrophils, monocytes, T cells, and NK cells into the peritoneum of CoH mice vs. SPF mice. This increased immune cell influx correlated with increased CXCL1 and CCL2 in peritoneal lavage samples from CoH mice. CoH mice devoid of neutrophils or LPM exhibit reduced cytokine storm and improved outcomes after sepsis induction. These data suggest the cells of the innate immune system govern the magnitude of the acute septic response.

Epigenetics of Sepsis.

Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures. Online search of published scientific literature via Pubmed using the term "epigenetics" in combination with the terms "sepsis", "infection", "bacterial infection", "viral infection", "critical illness", "acute respiratory distress syndrome", and "acute lung injury". Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles. Relevant data was extracted and synthesized for narrative review. Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1β. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury. Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers.

Elucidating the role of antibiotics on PAL release from E.coli

Sepsis can result from a systemic bacterial infection, followed by an over‐exuberant immune response, which leads to widespread inflammation. Severe sepsis can result in organ failure and in severe cases, death. Past studies have proposed a role for bacterial Peptidoglycan‐Associated Lipoprotein (Pal) in the pathogenesis of Gram‐negative bacterial sepsis. In this study, we confirmed that Pal is released from Gram‐negative bacteria, Escherichia coli (E. coli), under certain culture conditions, including in the presence of certain antibiotics. Our preliminary results suggest that different antibiotics have differential effects on Pal’s release from E.coli. Since the majority of sepsis patients are administered antibiotics, our findings may be of great significance to the medical field and the sepsis research community.Support or Funding InformationRIT FEAD/DRIG and NIH Bootcamp , RIT LSAMP program, Dr. Michael Pichichero Rochester General Hospital Research Institute

Core outcome set in paediatric sepsis in low- and middle-income countries: a study protocol

IntroductionSepsis is the leading cause of death in children worldwide and has recently been declared a major global health issue. New interventions and a concerted effort to enhance our understanding...

Evaluation and management of abdominal sepsis.

The review focuses on the evaluation and management of abdominal sepsis. A multitude of surgical approaches towards abdominal sepsis are practized in the world and may be associated with significant morbidity and mortality rates. Despite decades of sepsis research, no specific therapies for sepsis have emerged. Without specific therapies, the management of abdominal sepsis is based on the control of the infection and organ support. Early clinical diagnosis, adequate source control to stop ongoing contamination, appropriate antibiotic therapy dictated by patient and infection risk factors, and prompt resuscitation are the cornerstones of its management.